tbuckley/cabot-search huggingface dataset:
CTNI-58. UPDATED RESULTS AND MOLECULAR SUBGROUP ANALYSES FROM THE RANDOMIZED PHASE 3 MIRAGE TRIAL ON MARIZOMIB IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Patrick Roth, Thierry Gorlia, Jaap Reijneveld, Filip de Vos, Ahmed Idbaih, Jean-Sébastien Frenel, Emilie Le Rhun, Juan Sepúlveda, James Perry, G Laura Masucci, Pierre Freres, Hal Hirte, Clemens Seidel, Annemiek Walenkamp, Slavka Lukacova, Paul Meijnders, Andre Blais, Francois Ducray, Vincent Verschaeve, Garth Nicholas, Carmen Balana, Daniela Bota, Matthias Preusser, Sarah Nuyens, Fréderic Dhermain, Martin van den Bent, Chris J O’Callaghan, Maureen Vanlancker, Warren Mason, Michael Weller
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in numerous biological processes in tumors cells. Marizomib is a novel small molecule proteasome inhibitor that crosses the blood brain barrier and showed signs of activity in recurrent glioblastoma. METHODS EORTC 1709/CCTG CE.8 was a randomized, controlled, multicenter, open label phase 3 superiority trial. Major inclusion criteria were histologically confirmed newly diagnosed glioblastoma, age of 18 years or older and a Karnofsky performance status (KPS) &amp;gt; 70. Patients with tumors known to harbor an isocitrate dehydrogenase mutation were not eligible. RESULTS The trial was opened at 82 institutions in Europe, Canada and the US and 749 patients (of 750 planned) were randomized in a 1:1 ratio. Following a pre-planned interim analysis and a recommendation of the independent data monitoring committee, enrolment was discontinued. No significant difference in the median OS (mOS) was observed (standard arm: 17 months, marizomib arm: 16.5 months; p = 0.64; HR = 1.04). Median PFS was 6.0 vs. 6.3 months (p = 0.67; HR = 0.97). Patients with tumors harboring an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter had a mOS of 14.5 months in the standard therapy group and 15.1 months in the marizomib arm (p = 0.27, HR = 1.13). Among patients with an MGMT promoter-methylated tumor, median OS was 29.4 months in the marizomib arm and 25.5 months in the standard arm (p = 0.41, HR = 0.86). More CTCAE grade 3/4 treatment-emergent adverse events were noticed in the marizomib arm than in the standard arm. CONCLUSIONS The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status.
INNV-24. MACHINE LEARNING-BASED SPECTROSCOPIC TISSUE DIFFERENTIATION IN FLUORESCENCE-GUIDED NEUROSURGERY
Authors: David Black, Declan Byrne, Anna Walke, Sidong Liu, Antonio Di Ieva, Walter Stummer, Tim Salcudean, Eric Suero Molina
Journal: Neuro-Oncology (2023)

Abstract Maximal resection of malignant gliomas is hindered by difficulty in distinguishing tumor margins. Fluorescence-guided resection with 5-ALA assists in reaching this goal. Previously, we characterized five fluorophore emissions that accurately represent any spectrum measured from human brain tumor biopsies with a wide-field hyperspectral device. In this study, the effectiveness of these five spectra was explored for different tumor classification tasks in 891 hyperspectral widefield measurements of 184 patients harboring low- (n=30) and high-grade gliomas (n=115), non-glial primary brain tumors (n=19), radiation necrosis (n=2), miscellaneous (n=10) and metastases (n=8), which corresponds to up to 15000 spectra for a given test. The statistical differences in fluorophore abundances between classes were determined and visualized using dimensionality reduction techniques, including principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). Three machine-learning models were trained to classify tumor type (12 classes), grade (3 classes), and glioma margins (3 classes). Five algorithms were tested with varying hyperparameters for each classification task. We explored whether PCA projection onto five different axes than fluorophore abundances can provide more information for visualization and classification. The abundances of the five a priori fluorophore spectra matched or outperformed the five optimal PCA components for all classification tasks. These five axes capture 96-99% of the variance in the dataset. Using random forests and multilayer perceptrons, the classifiers achieved average test accuracies of 74-82%, 79%, and 81%, respectively. All five fluorophore abundances varied between tumor margin type as well as between grades (p &amp;lt; 0.01). For tissue type, at least four of five fluorophore abundances were found to be significantly different (p &amp;lt; 0.01) between all classes. These results demonstrate the differing contribution of fluorophores in different tissue classes tissue, as well as the five fluorophores value as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery.
CNSC-15. MITOCHONDRIA TRANSFER VIA GLIOMA-ASTROCYTE NETWORK MICROTUBES REPROGRAMS TUMOR CELLS FOR ENHANCED TUMORIGENICITY
Authors: Dionysios Watson, Defne Bayik, Simon Storevik, Shannon Moreino, Samuel Sprowls, Jianhua Han, Mina Augustsson, Adam Lauko, Sravya Palavalasa, Gro Rosland, Katie Troike, Karl Tronstad, Sabrina Wang, Katharina Sarnow, Kristen Kay, Taral Lunavat, Daniel Silver, Sahil Dayal, Justin Joseph, Erin Mulkearns-Hubert, Lars Ystaas, Gauravi Deshpande, Joris Guyon, Yadi Zhou, Capucine Magaut, Juliana Seder, Laura Neises, Sarah Williford, Johannes Meiser, Andrew J Scott, Peter Sajjakulnukit, Jason Mears, Rolf Bjerkvig, Abhishek Chakraborty, Thomas Daubon, Feixiong Cheng, Antonio Iavarone, Costas Lyssiotis, Daniel Wahl, Anita Hjelmeland, Jubayer Hossain, Hrvoje Miletic, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) interaction with neural cells is critical to its pathobiology. Emerging evidence suggests that GBM cells form an interconnected network with astrocytes, facilitating tumor persistence. Given reports of intercellular transfer of mitochondria in ischemic stroke and other pathologic disease states outside the CNS, we hypothesized that this network facilitates mitochondria transfer from astrocytes to GBM with protumorigenic sequelae. Employing transgenic mice and intracranial viral vector transductions in rats, we found that mitochondria transfer from the TME to GBM occurs in intracranial mouse and patient-derived xenograft models (in nude rats) of GBM. Mitochondria transfer from bone marrow-derived immune cells was minimal in bone marrow chimera mouse models of orthotopic GBM, suggesting that neural cells were the primary mitochondria donors. We confirmed this in vitro, where mouse astrocytes were the major mitochondria donors, followed by microglia and to a much smaller extent bone marrow-derived macrophages. Immortalized human astrocytes transduced with mitochondria-localized mCherry (mito-mCherry) also transferred their mitochondria to numerous patient-derived glioma stem cell (GSC) models at rates of ~5-20%, assessed by flow cytometry and confocal microscopy. Mitochondria were visualized along intercellular actin bridges, structurally resembling tumor microtubes. Blocking actin polymerization or knocking down GAP43 (previously linked to microtube formation) decreased mitochondria transfer from astrocytes to GBM in vitro. Functionally, sorted mito-mCherry+ patient-derived GSCs displayed higher mitochondrial respiration, metabolomic reprogramming and proliferation-promoting phospho-signaling. Mito-mCherry+ GBM cells were more likely to be in the proliferative G2/M phases of the cell cycle, and when sorted from co-cultures had high self-renewal (in vitro) and tumor-initiating capacity (in vivo xenograft mouse model). In ongoing work, we are investigating the role of retrograde GBM to astrocyte transfer of mitochondria by dual-color labeling of the organelle, as well as further delineating the protein machinery involved in this fundamental protumorigenic process, with the goal of identifying novel therapeutic targets.
Addition by Subtraction in Mechanical Cardiac Support
Authors: G. Michael Felker, Joseph G. Rogers
Journal: JAMA (2023)

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Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential
Authors: Martin T Henrich, Wolfgang H Oertel, D James Surmeier, Fanni F Geibl
Journal: Molecular Neurodegeneration (2023)

Abstract Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.
Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure
Authors: Mandeep R. Mehra, Ivan Netuka, Nir Uriel, Jason N. Katz, Francis D. Pagani, Ulrich P. Jorde, Finn Gustafsson, Jean M. Connors, Peter Ivak, Jennifer Cowger, John Ransom, Aditya Bansal, Koji Takeda, Richa Agarwal, Mirnela Byku, Michael M. Givertz, Abbas Bitar, Shelley Hall, Daniel Zimpfer, J. David Vega, Manreet K. Kanwar, Omar Saeed, Daniel J. Goldstein, Rebecca Cogswell, Farooq H. Sheikh, Matthew Danter, Yuriy Pya, Anita Phancao, John Henderson, Daniel L. Crandall, Kartik Sundareswaran, Edward Soltesz, Jerry D. Estep, Scott Silvestry, Antone Tatooles, Nasir Siulemanjee, Brett Sheridan, Sanjeev Gulati, Eugene Chung, Clement Delmas, Carmelo Milano, Pierre Dos Santos, Pavan Atluri, Douglas Horstmanshof, David D'Alessandro, Sriram Nathan, Peter Eckman, Anelechi Anyanwu, Anna Mara Scandroglio, Alessandro Ortalda, Ezequiel Molina, Jacob Abraham, Sern Lim, Robert Adamson, Ashwin Ravichandran, Christopher Hayward, William Hiesinger, John Entwistle, Jennifer Conway, Eric Adler, Jonathan Grinstein, Andreas Brieke, Mary Keebler, Jeffrey Alexis, Igor Gosev, Craig Selzman, David M Kaye
Journal: JAMA (2023)

Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety.
QOL-14. INTEGRATING A TECHNOLOGY-ENABLED PLATFORM FOR PATIENT REPORTED OUTCOMES INTO A NEURO-ONCOLOGY PRACTICE
Authors: Mariah Mahotz, Minhdan Nguyen, Renee George, Christine Swisher, Jason Weinreb, Yiqing Tang, Emmaline Mauritson, Naveed Wagle, Jose Carrillo, Neil Martin, Santosh Kesari, Akanksha Sharma
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Neuro-oncology (NOC) patients experience various symptoms from disease and treatment which are deleterious to function and quality of life (QOL). Evidence demonstrates the use of electronic patient-reported outcomes (ePROs) improves health-related QOL, mental functioning, patient-provider communication, and overall survival. Despite this knowledge, uptake across cancer services has been slow. In this pilot study, we sought to understand the utility of an electronic symptom monitoring platform (ESMP) in this population. METHODS We implemented an ESMP at a NOC practice and conducted a preliminary analysis of ePROs over 7-month period. Patients were prompted to report their symptoms at least 3 times/week through multiple-choice questions targeting 19 distinct symptoms and their severity (tiered 1-4). The care team was automatically notified through the electronic medical record predefined symptom severities. RESULTS During a 7-month period, 28 neuro-oncology patients were enrolled and monitored for a total of 660.7 patient-weeks or an average of 23.6 weeks per patient. In total, 314 questionnaires were completed; each patient completed 0.6 per week on average. We found questionnaire compliance to be the highest initially, declining in subsequent weeks. Symptoms were reported in 42.8% of questionnaires; the most frequent of which were peripheral neuropathy (16.6%), fatigue (11.5%) and headache (10.5%). Alerts were sent to the care team for 103 (32.8%) questionnaires, 38 resulted in additional interventions for the patient. CONCLUSION Our results support the hypothesis that technology-enabled integration of ePROs enables monitoring followed by automated alerts and customized responses to NOC patients. We note that peak usage was at the beginning of active treatment which occurred concurrently with onboarding. Opportunities and challenges involve the continuous promotion of patient engagement and optimization of workflow to encourage discussions and utilization. Future work also includes determining if this platform can lead to improved clinician efficiency and patient outcomes in this patient population.
CNSC-24. NEURONAL ACTIVITY PROMOTES GLIOMA PROGRESSION THROUGH INDUCING RNA M6A DEMETHYLATION AND PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOMA STEM CELLS
Authors: Xiaofan Guo, Qiu Wei, Gang Li
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas are lethal brain cancers whose progression is highly driven by neuronal activity. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and plays a significant role in the resistance of glioma to conventional therapies as well as cancer recurrence. Activity-regulated release of growth factors and electrical synaptic integration promotes glioma growth; however, it is unclear whether neuronal activity plays a role in the mRNA N6-methyladenosine (m6A) level changes in patient glioma tissue. By using chemogenetics techniques, we enhanced and inhibited neuronal activity in vitro and in vivo, and studied how neuronal activity regulates GSC behaviors. Here, we identified that neuronal activity promotes glioma progression and radioresistance through neuronal exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. We revealed that neuronal activity upregulates critical microRNA expression in NDEs (neuro-derived exosomes) and subsequently induces PMT by activating the STAT3 pathway. Chemogenetically activating cortical neurons increases the growth of GSC xenografts in situ. Conversely, reducing neuronal activity inhibited the GSC xenograft growth. Anti-seizure medication treatment suppresses GSC PMT and sensitizes GSCs to radiotherapy in vitro and in vivo. Together, these findings indicate that exosomes of active neurons can promote glioma progression and radioresistance by inducing GSC PMT via neuro-derived extracellular vesicles
IMMU-37. TARGETING NON-CATALYTIC ACTIVATORS OF THE PROTEASOME DECREASES TUMOR GROWTH AND ENHANCES ANTIGEN PRESENTATION IN GLIOBLASTOMA
Authors: Kyle Heemskerk, Xiaoguang Hao, Orsolya Cseh, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common adult primary brain tumor plagued by inevitable recurrence and poor survival. We recently performed a genome wide CRISPR/Cas9 essentiality screen in GBM stem cells, revealing a plethora of potential targets for further exploration. The proteasome is a multimeric protein complex that degrades cellular proteins contributing to homeostatic proteostasis, stress response, and antigen presentation. Most proteasomal subunits are essential for GBM stem cell growth in vitro, however, they are also essential for non-malignant neural cells, suggesting that inhibition of those subunits may lead to toxicity. Indeed, adverse neurological symptoms were prevalent in phase III clinical trials for the brain penetrant proteasome inhibitor, Marizomib, which may be linked to the vital role of proteasome subunits in non-malignant neural counterparts. Proteasome inhibitors target the catalytic subunits of the proteasome, however the role of individual proteasome activators, most of which are non-essential for growth in vitro, have not been fully elucidated in GBM. Here, we examined the functionality of non-essential proteasome activator subunits in GBM stem cells in vitro and in vivo. Surprisingly, despite lack of growth changes in vitro, we observed abrogated stem-cell self-renewal in vitro and improved survival in vivo in orthotopic xenograft models following targeting of specific activator subunits. Molecular profiling of targeted cells revealed an upregulation of interferon-γ signaling and upregulation of antigen presentation machinery. Thus, targeting specific activator subunits may inhibit malignant growth in vivo while sparing normal neural counterparts from proteotoxic stress. We are further investigating enhanced antigen presentation by targeting these proteasome activator subunits and examining changes in the tumor microenvironment and survival in syngeneic immunocompetent models of GBM. Further understanding of this mechanism may provide novel targets for GBM treatment or improve immunotherapies in GBM.
IMMU-31. B-CELL THERAPY (BVAX) PROMOTES CD8 T CELLS' PERSISTENCE AND FUNCTION IN THE GLIOBLASTOMA MICROENVIRONMENT BY MAINTAINING THEIR STEM-LIKE FEATURES
Authors: Hanxiao Wan, David Hou, Joshua Katz, Si Wang, Brandyn Castro, Tzu-Yi Chia, Gustavo Ignacio Vazquez Cervantes, Leah Billingham, Victor Arrieta, Yu Han, Aurora Lopez-Rosas, Peng Zhang, Jason Miska, Catalina Lee-Chang
Journal: Neuro-Oncology (2023)

Abstract The last decade witnessed tremendous improvement in immunotherapy to treat cancers. Its application in GBM has been particularly challenging due to the immunosuppressive tumor microenvironment, which greatly challenges T-cell infiltration and function. We developed a B-cell therapy with potent antigen-presenting functions that promote CD8+ tumor tropism and persistence in the tumor microenvironment. The present study investigates how BVax activates CD8+ T cells differently from other professional APCs like dendritic cells (DC) that could explain the persistence of CD8+ T cells in the tumor microenvironment. Upon in vitro activation by coculturing with BVax, most CD8+ T cells proliferated into TCF+ PD1- intermediate state, with CD44+ CD62L+ memory phenotype. Less than 10% of CD8+ were in the terminally-proliferation state. In contrast, DCs preferentially expanded TCF- PD1+ terminally-proliferating CD8+ T cells that were exhibiting CD44+ CD62L- effector phenotype. In vivo, activation of CD8+ T cells by co-injecting BVax or DC with CD8+ T cells to CT2A-bearing mice indicated that BVax promoted the proliferation of tumor-reactive CD8 T cells while maintaining the low PD1+ expression. Re-exposing the ex vivo-activated CD8+ T cells to tumor by adoptive transferring them to CT2A tumor-bearing mice revealed that BVax elicited immunological memory and potentiated GzmB+ production of CD8+ T cells. This study suggests that BVax and DC have distinctive interactions with CD8+ T cells, with the former poise CD8+ T cells at a more stem-like state, allowing them to differentiate upon tumor encounter.
SURG-25. SURGICAL MORBIDITY IN RELATION TO THE SURGICAL APPROACH FOR OLFACTORY GROOVE MENINGIOMAS—A POOLED ANALYSIS OF 1016 PATIENTS AND PROPOSAL OF A NEW REPORTING SYSTEM
Authors: Ekkehard Kasper, Farhan Mirza, Serdar Kaya, Robert Walker, Daniele Starnoni, Roy Daniel, Ramesh Nair, Fred Lam
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND There is no consensus regarding whether a frontal or lateral approach is superior for resection of olfactory groove meningiomas (OGM). Objective: 1) To compare surgical approaches for microsurgical resection of OGMs for extent of resection and complication rates. 2) To develop a novel preoperative scoring system to guide choice of approach to decrease surgical morbidity. METHODS A PRISMA-guided pooled analysis of 20,672 surgical reports on OGMs published in the MRI era using search terms such as ‘olfactory groove meningioma’ and ‘surgery’. After title screening and removal of duplicates, we assessed 871 studies on surgical management of OGMs. Following exclusion criteria, 27 studies were chosen for the final pooled cohort analysis of reported patient outcomes. RESULTS The 27 studies identified a total of 1,016 individual patients who underwent open microsurgical resection of OGMs. The approaches used included: pterional/unilateral, bifrontal with variations, and anterior interhemispheric approaches. Across all studies, gross total resection (Simpson Grades I or II) was achieved in 91.4% of cases, and subtotal resection (Grades III and IV) was reported in 8.6% of cases. A cumulative 27% of surgical OGM patients sustained some form of complications. Minor complications 22.2% (CSF leak, seizures, infection, transient cranial nerve palsies, hydrocephalus). Major complications 4.7% (hemorrhage, ischemic infarct, malignant cerebral edema). Correlation between complications and the surgical approach was performed. Among 426 patients who underwent unilateral approaches, 14% experienced minor complications, and 2.1% experienced major complications. The 410 patients who underwent bifrontal approaches, 24.6% experienced minor complications, and 7% experienced major complications. CONCLUSIONS Unilateral approaches appear to have lower complication rates than bilateral approaches, however, the extent of resection is not uniformly reported, making it difficult to identify differences. We herein propose a novel preoperative imaging-based classification scoring system to help select the most suitable surgical approach to achieve lower post-surgical complication rates.